1. Field of the Invention
The present invention relates to novel stabilized solutions and pharmaceutical compositions. The invention further relates to novel methods for stabilizing known pharmaceutical compositions.
In particular, the invention relates to stable pharmaceutical compositions of enol ether-containing prostacyclins. Further, the invention particularly relates to methods for stabilizing pharmaceutical compositions containing such prostacyclins.
Prostacyclin is an endogenously produced compound in mammalian species, being structurally and biosynthetically related to the prostaglandins (PG's). In particular, prostacyclin exhibits the following structure and carbon numbering: ##STR1##
5,6-Dihydroprostacyclin exhibits the following structure and carbon numbering: ##STR2## As is apparent from inspection of formulas I and II, prostacyclin and 5,6-dihydroprostacyclin (i.e., PGI.sub.1) bear a structural relationship to PGF.sub.2 .alpha., which exhibits the following structure and carbon numbering: ##STR3##
As is apparent by reference to formula III, prostacyclin and 5,6-dihydroprostacyclin may be trivially named as a derivative of PGF-type compounds. Accordingly, prostacyclin is trivially named 9-deoxy-6,9.alpha.-epoxy-(5Z)-5,6-didehydro-PGF.sub.1 and 5,6-dihydro prostacyclin is named 9-deoxy-6,9.alpha.-epoxy-PGF.sub.1. For description of the geometric stereoisomerism employed above, see Blackwood et al., Journal of the American Chemical Society 90, 509 (1968). Further, for a description of prostacyclin and its structural identification, see Johnson et al., Prostaglandins 12, 915 (1976).
When referred to herein, prostacyclin analogs will be referred to herein, prostacyclin analogs will be referred to by trivial, art-recognized system of nomenclature described by N. A. Nelson, Journal of Medicinal Chemistry, 17, 911 (1974) for the prostaglandins. Accordingly, all of the prostacyclin derivatives herein will be named as 9-deoxy-PGF.sub.1 -type compounds or alternatively and preferably as PGI.sub.1 or PGI.sub.2 derivatives.
Among the known analogs of prostacyclin or PGI.sub.2 are compounds wherein modifications are introduced into the C-12 side chain, the non-heterocyclic cyclopentane ring is optionally substituted or unsubstituted, or the carboxy-terminated side chain exhibits varying substituents on the C-4 to C-2 position. Such analogs of prostacyclin are described in U.S. Ser. No. 819,940, filed July 28, 1977.
Another class of prostacyclin analogs includes those which are epimeric to prostacyclin with respect to the C-5 unsaturation, and optionally contain other modifications as referred to in the preceding paragraph. Such analogs of prostacyclin are typified by (5E)-PGI.sub.2, a compound of the following formula: ##STR4## Such geometric isomers of prostacyclin are described in U.S. Ser. No. 775,003, filed Mar. 7, 1977.
Also known among the analogs of prostacyclin are compounds containing a 6-membered heterocyclic ring (instead of the 5-membered heterocyclic ring of prostacyclin) and optionally containing the various other analog features above. Such compounds are described in U.S. Ser. No. 819,856, filed July 28, 1977, and are typified by 9-deoxy-5,6.alpha.-epoxy-(4Z)-4,5-didehydro-PGF.sub.1, a prostacyclin analog of the following formula: ##STR5##
Yet another class of prostacyclin analogs is that wherein the 5-6 unsaturation of prostacyclin is isomerized to the 6,7-position. Such compounds, described in U.S. Ser. No. 860,673, filed Dec. 15, 1977, are typified by 6,7-didehydro-PGI.sub.1, a prostacyclin analog of the following formula: ##STR6##
Each of the foregoing prostacyclin analogs, except 5,6-dihydro prostacyclin (PGI.sub.1), is an enol-ether, which is relatively unstable in aqueous solutions. As is known in the art, enol ethers typically hydrolyze in aqueous solutions, an effect which may severely limit the time interval between the preparation of such an aqueous solution and its subsequent use, e.g., for intravenous infusion. For example, in neutral and acidic solutions, prostacyclin is known to rapidly hydrolyze to 6-keto-PGF.sub.1 .alpha.. See the paper of M. J. Cho and M. A. Allen in Prostaglandins (1978), and various references cited therein.
Notwithstanding the relative instability of prostacyclin and related analogs in solution, pharmaceutical compositions for parenteral administration of these compounds are known in the art and are known to be useful in the induction of prostacyclin - like pharmacological effects. See particularly the various U.S. patent application referred to above, the relevant disclosure of which with respect to compositions and methods for parenteral administration of these compounds is incorporated herein by reference.
There are further known in the art surfactants exhibiting a wide range of structural variation. Surfactants are known in the art and defined in the art to be surface-active organic compounds, which are capable of modifying the surface tension of aqueous solutions in which they are present. A determination of whether an organic compound is indeed a surfactant is readily assessed by the effect of that compound on the surface tension of an aqueous solution by methods known in the art. See for example Rowe, E. L., "Automated Drop Volume Apparatus for Surface Tension Measurement", J. Pharm. Sci., 61:781-782 (1972).
While a wide variety of surfactants is known in the art, including detergents and the like, a more limited variety of surface-active agents have potential utility in pharmaceutical preparations. Among these are the various surfactants described by Charnicki, W. F., Am. J. Pharm. 409 (1958); Mulley, V. A., et al., Adv. Pharm. Sci. 1:87 (1964); and, Mukerjee, P., et al., "Critical Micelle Concentrations of Aqueous Surfactant Systems", U.S. Government Printing Office, Washington, D.C., 1971.
The various surfactants known in the art exhibit a concentration dependent modification of surface tension when in aqueous solution. Typically, surface tension will decrease as the concentration of surfactant increases, until a "critical micellar concentration" (CMC) is reached. Increasing the concentration of surfactant beyond the CMC typically causes no further reduction in surface tension.
Accordingly, for any surfactant, the CMC is readily determined by measuring the surface tension (e.g., the method of Rowe, cited above) and determining the lowest concentration at which the marginal change in surface tension is zero.
Finally, numerous categories of surfactants are known in the art. Typically, surfactants are categorized by whether or not they contain ionic functional groups. Accordingly, there are known both neutral and ionic surfactants and ionic surfactants are further categorized as being either cationic or anionic. As the same suggests, cationic surfactants contain at least one electron-deficient (positively charged) functional group, while anionic surfactants contain at least one electron-enriched (negatively charged) functional group. Otherwise, surfactants are typically characterized by relatively long chained carbon backbones, providing a hydrophobic region.
Prior Art
Numerous methods for the stabilization of relatively unstable prostaglandins are known in the art. For example, the use of cyclodextrin clathrates for the stabilization of prostaglandins is described in Belgian Pat. No. 768,288 (Derwent Farmdoc CPI No. 80084S-B). Further, the stabilization of PGE.sub.2 (Prostaglandin E.sub.2) in anhydrous alcohol is described in U.S. Pat. No. 3,749,800, while the stabilization of PGE.sub.2 in polar, aprotic solvents is described in U.S. Pat. No. 3,829,579. Further, the use of surfactants to prevent the C-15 epimerization of 15-methyl-PGF.sub.2 .alpha. is reported in Allen, M. A., "The Effects of Surfactants on the Epimerization of 15(S) 15-methyl-PGF.sub.2 .alpha.", a B.A. dissertaion submitted to Kalamazoo College, Kalamazoo, Mich. in 1977.
Further, the use of surfactants to catalyze or inhibit chemical reactions is known in the art. Discussions of the catalytic effects of surfactants on chemical reactions is described in Tanford, C., "The Hydrophobic Effect Formation of Micelles and Biological Membranes", Wiley and Sons, New York, N.Y., 1973; Bunton, C. A., Prog. Sol. St. Chem. 8:239 (1973); Cordes, B., "Reactions Kinetics in Micelles", Plenum Press, New York, N.Y., 1973; Fendler, J. H., et al., "Catalysis in Micellar and Macromolecular Systems", Academic Press, New York, N.Y., 1975; Piszkiewicz, D., Journal of Am. Chem. Soc. 99:1550 (1977); and, Dougherty, S. J., et al., "On the Prediction of Reaction Rate in Micellar Solutions", J. Coll. Int. Sci., 49:135-138 (1974).
Regarding the inhibition of chemical reactions in surfactant-containing aqueous solutions, see Bunton, C. A., "Micellar Catalysis and Inhibition", Progress in Solid-State Chemistry, Vol., 8; McCaldin, J. O., Ed., Pergamon Press, New York, N.Y. (pp 239-281); and, Mitchell, A. G., "The Hydrolysis of Propylbenzoate in Aqueous Solutions of Cetomacrogol", J. Pharm. Pharmacol., 15:761-765 (1963); and, Cho, M. J., et al, "Quantative Assessment of the Negative Catalytic Effects of a Cationic Surfactant Myristyl-.gamma.-Picolinium Chloride on the Specific-Acid Catalyzed Epimerization of 15(S) 15-methyl PGF.sub.2 .alpha.", in the June, 1978, issue of Intl. J. Pharm.